Our objective is to elucidate how cells derived the mammalian brain perceive and respond to the signals in their environment. We have studied the effects of hormones and neurotransmitters which transmit information across the plasma membrane while binding to and remaining at cell-surface receptors. In neurons cultured from the cerebellum of neonatal rats, we have shown that the ability of synthesize the second messenger cyclic GMP in response to excitatory amino acids is related to the developmental stage of the neuron, is mediated by the influx of calcium ions, and may be modulated by calmodulin. We have shown that the stimulation of guanylate cyclase by glutamate in cerebellar neurons occurs via the NMDA-subtype of glutamate receptor; when occupied by an appropriate agonist, the receptor opens a sodium-calcium channel which is blocked by magnesium in a voltage-dependent manner. We have now found that the magnesium block is sensitive to the energy level of the cell; decreases in adenine nucleotide levels due to glucose starvation, oxygen deprivation, or metabolic poisons cause sufficient depolarization to relieve the magnesium block of the NMDA receptor channel enabling glutamate to persistently open the channel resulting in excession influx and cell death. Our results provide experimental evidence for a mechanism which may trigger the transition of glutamate from neurotransmitter to neurotoxin which underlies a variety of neurological disorders.